Implantable or insertable medical device resistant to microbial growth and biofilm formation

ABSTRACT

Disclosed are implantable or insertable medical devices that provide resistance to microbial growth on and in the environment of the device and resistance to microbial adhesion and biofilm formation on the device. In particular, the invention discloses implantable or insertable medical devices that comprise at least one biocompatible matrix polymer region, an antimicrobial agent for providing resistance to microbial growth and a microbial adhesion/biofilm synthesis inhibitor for inhibiting the attachment of microbes and the synthesis and accumulation of biofilm on the surface of the medical device. Also disclosed are methods of manufacturing such devices under conditions that substantially prevent preferential partitioning of any of said bioactive agents to a surface of the biocompatible matrix polymer and substantially prevent chemical modification of said bioactive agents

STATEMENT OF RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/040,864, filed Jan. 21, 2005, the disclosure of which is herebyincorporated by reference in its entirety, which is a divisional U.S.patent application Ser. No. 10/071,840, filed Feb. 8, 2002, now U.S.Pat. No. 6,887,270, issued May 3, 2005 entitled “Implantable OrInsertable Medical Device Resistant To Microbial Growth and BiofilmFormation,” which is incorporated by reference in its entirety herein.

FIELD OF THE INVENTION

The present invention relates to implantable or insertable medicaldevices that provide resistance to microbial growth on and in theenvironment of the device and resistance to microbial adhesion andbiofilm formation on the device. In another aspect, the presentinvention relates to methods of manufacturing such implantable orinsertable medical devices, particularly to methods of manufacturingsuch devices that comprise at least one matrix polymer region, anantimicrobial agent for providing resistance to microbial growth and amicrobial adhesion/biofilm synthesis inhibitor for inhibiting theattachment of microbes and the synthesis and accumulation of biofilm onthe surface of the medical device.

BACKGROUND OF THE INVENTION

Implantable or insertable medical devices such as stents made ofmetallic, polymeric or a composite of metallic and polymeric materialsfrequently occlude due to microbial colonization and adhesion. Thisproblem is particularly prevalent with medical devices that are adaptedto remain implanted for a relatively long-term, i.e., from about 30 daysto about 12 months or longer. Microbes such as bacteria often colonizeon and around the medical device and, upon attaching to surfaces of thedevice, proliferate and form aggregates within a complex matrixconsisting of extracellular polymeric substances, typicallypolysaccharides. The mass of attached microorganisms and the associatedextracellular polymeric substances is commonly referred to as a biofilmor slime. Antimicrobial agents have difficulty penetrating biofilms andkilling and/or inhibiting the proliferation of the microorganisms withinthe biofilm. The colonization of the microbes on and around the deviceand the synthesis of the biofilm barrier eventually result inencrustation, occlusion and failure of the device.

Previous approaches to minimize this problem have included the use oflow surface energy materials such as Teflon® in implantable medicaldevices and the use of surface coatings on such medical devices. Surfacecoatings have typically comprised single antimicrobials or 1-2antibiotics.

For example, U.S. Pat. No. 5,853,745 discloses an implantable medicaldevice having a durable protective coating layer over an antimicrobialcoating layer. The coating layers are formed by applying anantimicrobial coating layer to at least a portion of the surface of themedical device, applying a durable coating over the antimicrobialcoating layer, and applying a resilient coating layer over the durablecoating layer.

U.S. Pat. No. 5,902,283 discloses a non-metallic antimicrobialimpregnated implantable medical device where the antimicrobialcomposition is applied to the device under conditions where theantimicrobial composition permeates the material of the device.

U.S. Pat. No. 5,772,640 discloses polymeric medical devices that havebeen impregnated and/or coated with chlorhexidine and triclosan bydipping or soaking the medical device in a solution of a hydrophobic orhydrophilic polymer containing chlorhexidine and triclosan.

Published International Application No. WO 99/47595 discloses a plasticsmaterial that can be used in certain medical applications comprising anacrylic polymer containing 5-50% of a rubbery copolymer and a biocidalcompound. The patent also discloses adding antimicrobial agent to thepolymer melt by means of a liquid injection system.

U.S. Pat. No. 5,679,399 discloses membranes that may include one or morepermeable or semipermeable layers containing substances such asbiocides. The layers allow the transmission of environmental fluidsinwardly and the outward dispersion of the biocides. These membranes mayalso include a sealing or coating to entrap agents such as biocidestherein.

Of the previous approaches, coatings have met with the greatest successbecause of their proximity to the bacterial environment and hence theiractive approach to preventing bacterial colonization and attachment.However, this approach has proven inadequate because of the potentialfor bacterial resistance to a single narrow spectrum active agent,because the amount of active agent that can be incorporated into suchcoatings is typically low, and because externally coated tubular devicesrelease active agents to the environment external to the device but notintraluminally.

In an effort to alleviate the foregoing and other disadvantages of theprior art, Applicants have developed an implantable or insertablemedical device suitable for long-term implantation and a method formanufacturing such a device, wherein the device provides resistance tomicrobial growth on and around the device and biofilm formation on thedevice. The device of the present invention, therefore, overcomes thedisadvantages associated with the use of coatings as discussed above,and provides a reduced risk of biofilm fouling that eventually resultsin encrustation, occlusion and failure of the device.

SUMMARY OF THE INVENTION

One aspect of the present invention is directed to an implantablemedical device comprising at least one biocompatible matrix polymerregion and bioactive agents comprising an antimicrobial agent and amicrobial attachment/biofilm synthesis inhibitor. In some preferredembodiments, the medical device comprises multiple distinct matrixpolymer regions. One or more barrier layers at least partially coveringa matrix polymer region may also be provided in preferred embodiments ofthe present invention. Preferred antimicrobial agents include triclosan,chlorhexidine and salts or combinations thereof. Other antimicrobialagents include, but are not limited to nitrofurazone, benzalkoniumchlorides, silver salts and antibiotics such as rifampin, gentamycin andminocyclin. Preferred microbial attachment/biofilm synthesis inhibitorsinclude salicylic acid and salts and derivatives thereof. Aradio-opacifying agent is preferably included in a matrix polymerregion, and one or more therapeutic agents may also be present. Thematrix polymer and any barrier layer may preferably comprise abiodegradable or substantially non-biodegradable material such as anethylene vinyl acetate copolymer, copolymers of ethylene with acrylicacid or methacrylic acid; metallocene catalyzed polyethylenes andpolyethylene copolymers, ionomers, elastomeric materials such aselastomeric polyurethanes and polyurethane copolymers, silicones andmixtures thereof. Among medical devices in accordance with the presentinvention are biliary, ureteral and pancreatic stents, stent covers,catheters, venous access devices and devices bridging or providingdrainage between a sterile and non-sterile body environment or betweentwo sterile body environments. Pancreatic stents that release abuffering agent are among preferred pancreatic stents.

In another aspect, the present invention is directed to a method ofmanufacturing an implantable or insertable medical device comprisingproviding one or more biocompatible matrix polymers and bioactive agentscomprising an antimicrobial agent and a microbial attachment/biofilmsynthesis inhibitor; processing the one or more biocompatible matrixpolymers and the bioactive agents under conditions that substantiallyprevent preferential partitioning of any of the bioactive agents to asurface of any of the biocompatible matrix polymers and substantiallyprevent chemical modification of the bioactive agents. Processingpreferably comprises forming a homogenous mixture of the matrix polymerand any bioactive agent and optional radio-opacifying agent and/ortherapeutic agent and shaping the homogeneous mixture into at least aportion of an implantable or insertable medical device. Among preferredshaping processes are included extrusion and coextrusion for multiplelayer structures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a simplified schematic representation (perspective view) of aportion of an implantable or insertable medical device in accordancewith an embodiment of the present invention.

FIG. 2 is a simplified schematic representation (perspective view) of aportion of an implantable or insertable medical device in accordancewith an embodiment of the present invention.

FIG. 3 is a graph showing bacterial attachment inhibition onto extrudedtubes containing varying amounts of triclosan (TCN) and salicylic acid(SA).

FIG. 4 is a graph showing bacterial attachment inhibition onto extrudedtubes containing varying amounts of triclosan (TCN) and salicylic acid(SA).

FIG. 5 is a graph showing the zone of bacterial (E. coli ATCC 25922)growth inhibition around extruded tubes containing varying amounts oftriclosan (TCN) and salicylic acid (SA).

FIG. 6 is a graph showing the zone of bacterial (coagulase negativestaph #99) growth inhibition around extruded tubes containing varyingamount of triclosan and salicylic acid (SA).

As is typically the case with such figures, FIGS. 1 and 2 are simplifiedschematic representations presented for purposes of illustration only,and the actual structures may differ in numerous respects including therelative scale of the components.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention is directed to an implantable orinsertable medical device comprising at least one biocompatible matrixpolymer region, as well as multiple bioactive components, which comprisean antimicrobial agent and a microbial attachment/biofilm synthesisinhibitor.

The term “biocompatible” as used herein describes a material that issubstantially not toxic to the human body, and that does notsignificantly induce inflammation or other adverse response in bodytissues.

The term “matrix polymer” as used herein refers to a polymeric materialthat forms at least a portion or region of the implantable or insertablemedical device of the present invention. The matrix polymer is selectedto be biocompatible and provide mechanical properties consistent withthe intended function and operation of the implantable or insertablemedical device. The matrix polymer also serves as a repository in whichat least one and, in some preferred embodiments, both the antimicrobialagent and microbial attachment/biofilm synthesis inhibitor are dispersedand/or dissolved. The matrix polymer may also contain, as optionalcomponents, a radio-opacifying agent and/or one or more therapeuticagents.

The term “antimicrobial agent” as used herein means a substance thatkills and/or inhibits the proliferation and/or growth of microbes,particularly bacteria, fungi and yeast. Antimicrobial agents, therefore,include biocidal agents and biostatic agents as well as agents thatpossess both biocidal and biostatic properties. In the context of thepresent invention, the antimicrobial agent kills and/or inhibits theproliferation and/or growth of microbes on and around the surfaces of animplanted medical device.

The term “microbial attachment/biofilm synthesis inhibitor” as usedherein means a substance that inhibits the attachment of microbes onto asurface and the ability of such microbes to synthesize and/or accumulatebiofilm on a surface. In the context of the present invention, such asurface includes a surface of an implantable medical device exposed to aphysiological environment, such as a physiological fluid, that may beconducive to the formation and accumulation of biofilm on the surface ofthe medical device. The microbial attachment/biofilm synthesis inhibitormay also have substantial antimicrobial activity as described herein.Likewise, the antimicrobial agent may also have substantial ability toinhibit microbial attachment/biofilm synthesis.

By “biofilm” is meant the mass of microorganisms attached to a surface,such as a surface of a medical device, and the associated extracellularsubstances produced by one or more of the attached microorganisms. Theextracellular substances are typically polymeric substances and commonlycomprise a matrix of complex polysaccharides, proteinaceous substancesand glycopeptides. This matrix or biofilm is also commonly referred toas “glycocalyx.”

Biofilm formation on the surfaces of implantable or insertable medicaldevices adapted for long-term implantation, e.g., from about 30 days to12 months or longer, can result in eventual encrustation and failure ofthe device. Further, the proliferation of microbes within the biofilmcan lead to localized infections as well as difficult to treat systemicinfections. The extracellular substances that comprise the biofilmmatrix can act as a barrier that protects and isolates themicroorganisms housed in the biofilm from normal immunological defensemechanisms, such as antibodies and phagocytes, as well as fromantimicrobial agents including surfactants, biocides and antibiotics.The biofilm also facilitates the growth and proliferation of microbeshoused within the biofilm.

The present invention substantially reduces the risk of biofilmaccumulation on the surfaces of a medical device adapted for long termimplantation, and the resultant likelihood of premature failure of thedevice due to encrustation and occlusion by such biofilm. In somepreferred embodiments of the present invention, the medical device isintended to remain implanted for a relatively long period of from about30 days to about 12 months or longer. However, it is understood that thedevice may be implanted for a period of 30 days or shorter as well.

The biocompatible matrix polymer of the device of the present inventionis provided to serve as a repository in which the antimicrobial agent,the microbial attachment/biofilm synthesis inhibitor, or both, aredispersed and/or dissolved. The medical device of the present inventionwill preferably contain at least one matrix polymer which forms at leasta single distinct portion or region of the medical device. Where only asingle distinct matrix polymer region is provided in the medical device,the matrix polymer will preferably contain both the antimicrobial agentand the microbial attachment/biofilm synthesis inhibitor. However, inother preferred embodiments, the medical device will comprise two ormore distinct matrix polymer regions. Where two or more distinct matrixpolymer regions are present in the medical device, it is not necessarythat both the antimicrobial agent and the microbial attachment/biofilmsynthesis inhibitor be present in any single one of such multiple matrixpolymer regions. Thus, the antimicrobial agent may be present in a firstmatrix polymer region and the microbial attachment/biofilm synthesisinhibitor may be present in a second matrix polymer region distinct fromthe first matrix polymer region. However, it is understood that bothbioactive agents may be present in one or all of any distinct matrixpolymer regions. Further, as discussed more fully below, where multipledistinct matrix polymer regions are present, the regions may beseparated by barrier layers that at least partially cover a surface ofthe matrix polymer region.

The amount of the antimicrobial agent present in a matrix polymer ispreferably an amount effective to kill and/or inhibit the growth ofmicrobes on and around the implanted medical device. Preferred amountsof the antimicrobial agent present in the matrix polymer range fromabout 0.5% to about 25% by weight of the matrix polymer. Amounts of fromabout 10% to about 25% by weight of the matrix polymer are particularlypreferred.

The amount of the microbial attachment/biofilm synthesis inhibitorpresent in a matrix polymer is preferably an amount effective to inhibitthe attachment of microbes onto and the synthesis and/or accumulation ofbiofilm by attached microbes on a surface of the implanted medicaldevice. Preferred amounts of the antimicrobial agent present in thematrix polymer range from about 0.5% to about 25% by weight of thematrix polymer. Amounts of from about 10% to about 25% by weight of thematrix polymer are particularly preferred.

The amount of antimicrobial agent and/or microbial attachment/biofilmsynthesis inhibitor present in a matrix polymer will depend on, interalia, on the efficacy of the bioactive agent employed, the length oftime during which the medical device is intended to remain implanted, aswell as the rate at which the matrix polymer or barrier layer releasesthe bioactive agent in the environment of the implanted medical device.Thus, a device that is intended to remain implanted for a longer periodwill generally require a higher percentage of the antimicrobial agentand/or microbial attachment/biofilm synthesis inhibitor. Similarly, amatrix polymer that provides faster release of the bioactive agent mayrequire a higher amount of the bioactive agent. The amount of bioactiveagent in the matrix polymer may be limited, of course, by the propensityfor such bioactive agent to cause undesirable localized or systemictoxic reaction and by the potential impairment of the mechanicalproperties necessary for the proper functioning of the medical device.

In many instances, it is believed that the bioactive agent is released,at least in part, from a non-biodegradable matrix polymer region by amechanism wherein the matrix polymer imbibes or contacts physiologicalfluid. The physiological fluid dissolves or disperses the bioactiveagent reposed within the matrix, and the dissolved or dispersedbioactive agent then diffuses outwardly from the matrix polymer into thephysiological environment where the device is implanted. Matrix polymersneed not be permeable to aqueous fluids such as physiological fluids toprovide release of bioactive agent. Matrix polymers with lowpermeability to aqueous fluids may adsorb such fluids at a surface ofthe polymer. In such matrix polymers, a concentration gradient isbelieved to be set up at the surface of the polymer and the bioactiveagent is released via diffusion based on its solubility in the solidpolymer relative to its solubility in the fluid or aqueous phase. Wherethe matrix polymer is biodegradable, similar diffusion processes mayalso occur. In a biodegradable matrix polymer, bioactive agent may alsobe released as the biodegradable matrix polymer containing the reposedbioactive agent biodegrades upon contact with the physiologicalenvironment where the device is implanted. Thus, in a biodegradablepolymer, bioactive agent may be released by diffusional processes andupon biodegradation of the polymer matrix.

The antimicrobial agent present in the matrix polymer can be anypharmaceutically acceptable antimicrobial agent. By “pharmaceuticallyacceptable” as used herein is meant an agent that is approved or capableof being approved by the United States Food and Drug Administration orDepartment of Agriculture as safe and effective for use in humans oranimals when incorporated in or on an implantable or insertable medicaldevice. Preferred antimicrobial agents include, but are not limited to,triclosan, chlorhexidine, nitrofurazone, benzalkonium chlorides, silversalts and antibiotics such as rifampin, gentamycin and minocyclin andcombinations thereof.

The microbial attachment/biofilm synthesis inhibitor can be anypharmaceutically acceptable agent that inhibits the attachment ofmicrobes onto and the synthesis and/or accumulation of biofilm on asurface of an implantable or insertable medical device. Among preferredmicrobial attachment/biofilm synthesis inhibitors include, but are notlimited to, non-steroidal anti-inflammatory drugs (NSAIDs) and chelatingagents such as EDTA (ethylenediaminetetraacetic acid), EGTA(O,O′-bis(2-aminoethyl)ethyleneglycol-N,N,N′,N′-tetraacetic acid) andmixtures thereof. Among preferred NSAIDs are salicylic acid and saltsand derivatives thereof. Preferred salts of salicylic acid include, butare not limited to, sodium salicylate and potassium salicylate. Sodiumsalicylate is a particularly preferred salt for use as the microbialattachment/biofilm synthesis inhibitor. Salicylic acid is a particularlypreferred microbial attachment/biofilm synthesis inhibitor.

Some preferred combinations of antimicrobial agent and microbialattachment/biofilm synthesis inhibitors present in a medical device inaccordance with the present invention comprise triclosan and/orchlorhexidine in combination with salicylic acid or a salt thereof suchas sodium salicylate. The combination of triclosan and salicylic acid ora salt thereof is particularly preferred.

The presence of both an antimicrobial agent and a microbialattachment/biofilm synthesis inhibitor in a medical device in accordancewith the present invention provides distinct advantages over the use of,for example, only an antimicrobial agent. The use of such a dualmechanism for preventing microbial colonization and attachment isbelieved to have a synergistic effect. The synergy is related to thedifferent mechanism of action of each of the bioactive agents. Theantimicrobial agent not only kills a large percentage of microbesapproaching a surface of the device, it also reduces the burden ofmicrobes upon which the microbial attachment/biofilm synthesis inhibitormust act. Moreover, microbes that have attached to a surface produce aprotective biofilm barrier after attachment. This biofilm barrierprevents or reduces the ability of antimicrobial agents from reachingthe microbes. The antimicrobial agent is thereby rendered substantiallyless effective upon formation of the biofilm barrier. Therefore, ifmicrobial attachment is prevented, biofilm synthesis is inhibited andthe antimicrobial agent is rendered more effective.

The matrix polymer used in the implantable or insertable medical deviceof the present invention may be any biocompatible polymer suitable foruse in implantable or insertable medical devices. The matrix polymer maybe substantially non-biodegradable or biodegradable.

Preferred substantially non-biodegradable biocompatible matrix polymersinclude thermoplastic and elastomeric polymeric materials. Polyolefinssuch as metallocene catalyzed polyethylenes, polypropylenes, andpolybutylenes and copolymers thereof; vinyl aromatic polymers such aspolystyrene; vinyl aromatic copolymers such as styrene-isobutylenecopolymers and butadiene-styrene copolymers; ethylenic copolymers suchas ethylene vinyl acetate (EVA), ethylene-methacrylic acid andethylene-acrylic acid copolymers where some of the acid groups have beenneutralized with either zinc or sodium ions (commonly known asionomers); polyacetals; chloropolymers such as polyvinylchloride (PVC);fluoropolymers such as polytetrafluoroethylene (PTFE); polyesters suchas polyethyleneterephthalate (PET); polyester-ethers; polyamides such asnylon 6 and nylon 6,6; polyamide ethers; polyethers; elastomers such aselastomeric polyurethanes and polyurethane copolymers; silicones;polycarbonates; and mixtures and block or random copolymers of any ofthe foregoing are non-limiting examples of non-biodegradablebiocompatible matrix polymers useful for manufacturing the medicaldevices of the present invention.

Among particularly preferred non-biodegradable polymeric materials arepolyolefins, ethylenic copolymers including ethylene vinyl acetatecopolymers (EVA) and copolymers of ethylene with acrylic acid ormethacrylic acid; elastomeric polyurethanes and polyurethane copolymers;metallocene catalyzed polyethylene (mPE), mPE copolymers, ionomers, andmixtures and copolymers thereof; and vinyl aromatic polymers andcopolymers. Among preferred vinyl aromatic copolymers are includedcopolymers of polyisobutylene with polystyrene or polymethylstyrene,even more preferably polystyrene-polyisobutylene-polystyrene triblockcopolymers. These polymers are described, for example, in U.S. Pat. No.5,741,331, U.S. Pat. No. 4,946,899 and U.S. Ser. No. 09/734,639, each ofwhich is hereby incorporated by reference in its entirety. Ethylenevinyl acetate having a vinyl acetate content of from about 19% to about28% is an especially preferred non-biodegradable material. EVAcopolymers having a lower vinyl acetate content of from about 3% toabout 15% are also useful in particular embodiments of the presentinvention as are EVA copolymers having a vinyl acetate content as highas about 40%. These relatively higher vinyl acetate content copolymersmay be beneficial in offsetting stiffness from coextruded barrierlayers. Among preferred elastomeric polyurethanes are block and randomcopolymers that are polyether based, polyester based, polycarbonatebased, aliphatic based, aromatic based and mixtures thereof.Commercially available polyurethane copolymers include, but are notlimited to, Carbothane®, Tecoflex®, Tecothane®, Tecophilic®, Tecoplast®,Pellethane®, Chronothane® and Chronoflex®. Other preferred elastomersinclude polyester-ethers, polyamide-ethers and silicone.

Among preferred biodegradable matrix polymers are included, but notlimited to, polylactic acid, polyglycolic acid and copolymers andmixtures thereof such as poly(L-lactide) (PLLA), poly(D,L-lactide)(PLA); polyglycolic acid [polyglycolide (PGA)],poly(L-lactide-co-D,L-lactide) (PLLA/PLA), poly(L-lactide-co-glycolide)(PLLA/PGA), poly(D, L-lactide-co-glycolide) (PLA/PGA),poly(glycolide-co-trimethylene carbonate) (PGA/PTMC),poly(D,L-lactide-co-caprolactone) (PLA/PCL),poly(glycolide-co-caprolactone) (PGA/PCL); polyethylene oxide (PEO),polydioxanone (PDS), polypropylene fumarate, poly(ethylglutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethylglutamate), polycaprolactone (PCL), polycaprolactone co-butylacrylate,polyhydroxybutyrate (PHBT) and copolymers of polyhydroxybutyrate,poly(phosphazene), polyphosphate ester), poly(amino acid) andpoly(hydroxy butyrate), polydepsipeptides, maleic anhydride copolymers,polyphosphazenes, polyiminocarbonates, poly[(97.5% dimethyl-trimethylenecarbonate)-co-(2.5% trimethylene carbonate)], cyanoacrylate,polyethylene oxide, hydroxypropylmethylcellulose, polysaccharides suchas hyaluronic acid, chitosan and regenerate cellulose, and proteins suchas gelatin and collagen, and mixtures and copolymers thereof, amongothers.

Particularly preferred biodegradable polymers comprise polylactic acid,polyglycolic acid and copolymers and mixtures thereof.

The medical device of the present invention may also contain aradio-opacifying agent within its structure. For example, theradio-opacifying agent may be present in or on any of the matrix polymerregions or in or on an optional barrier layer that at least partiallycovers a surface of a matrix polymer region. Barrier layers aredescribed more fully below. The radio-opacifying agent facilitatesviewing of the medical device during insertion of the device and at anypoint while the device is implanted. A radio-opacifying agent typicallyfunctions by scattering x-rays. The areas of the medical device thatscatter the x-rays are detectable on a radiograph. Amongradio-opacifying agents useful in the medical device of the presentinvention are included, but not limited to, bismuth subcarbonate,bismuth oxychloride, bismuth trioxide, barium sulfate, tungsten andmixtures thereof. Where present, the radio-opacifying agent ispreferably present in an amount of from about 0.5% to about 90%, morepreferably from about 10% to about 90% by weight, of the matrix polymer.A particularly preferred amount of radio-opacifying agent is from about10 to about 40% by weight of the matrix polymer.

The medical device of the present invention may also contain one or moretherapeutic agents within its structure. For example, any therapeuticagent may be present in or on any of the matrix polymer regions or in oron any optional barrier layer that at least partially covers a surfaceof a matrix polymer region. The therapeutic agent may be anypharmaceutically acceptable agent. A therapeutic agent includes genetictherapeutic agents, non-genetic therapeutic agents and cells.

Exemplary non-genetic therapeutic agents include: (a) anti-thromboticagents such as heparin, heparin derivatives, urokinase, and PPack(dextrophenylalanine proline arginine chloromethylketone); (b) steroidaland non-steroidal anti-inflammatory agents (NSAIDs) such asdexamethasone, prednisolone, corticosterone, hydrocortisone andbudesonide estrogen, sulfasalazine and mesalamine, salicylic acid andsalts and derivatives thereof, ibuprofen, naproxen, sulindac,diclofenac, piroxicam, ketoprofen, diflunisal, nabumetone, etodolac,oxaprozin and indomethacin; (c) chemotherapeutic agents such asantineoplastic/antiproliferative/anti-mitotic agents includingpaclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,epothilones, endostatin, angiostatin, doxorubicin, methotrexate,angiopeptin, monoclonal antibodies capable of blocking smooth musclecell proliferation, and thymidine kinase inhibitors; (d) anestheticagents such as lidocaine, bupivacaine and ropivacaine; (e)anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGDpeptide-containing compound, heparin, hirudin, antithrombin compounds,platelet receptor antagonists, anti-thrombin antibodies, anti-plateletreceptor antibodies, aspirin, prostaglandin inhibitors, plateletinhibitors and tick antiplatelet peptides; (f) vascular cell growthpromoters such as growth factors, transcriptional activators, andtranslational promotors; (g) vascular cell growth inhibitors such asgrowth factor inhibitors, growth factor receptor antagonists,transcriptional repressors, translational repressors, replicationinhibitors, inhibitory antibodies, antibodies directed against growthfactors, bifunctional molecules consisting of a growth factor and acytotoxin, bifunctional molecules consisting of an antibody and acytotoxin; (h) protein kinase and tyrosine kinase inhibitors (e.g.,tyrphostins, genistein, quinoxalines); (i) prostacyclin analogs; (j)cholesterol-lowering agents; (k) angiopoietins; (l) antimicrobial agentssuch as triclosan, cephalosporins, β-lactams, aminoglycosides andnitrofurantoin; (m) chemotherapeutic agents such as cytotoxic agents,cytostatic agents and cell proliferation affectors; (n) vasodilatingagents; and (o) agents that interfere with endogenous vascoactivemechanisms.

Exemplary genetic therapeutic agents include anti-sense DNA and RNA aswell as DNA coding for: (a) anti-sense RNA, (b) tRNA or rRNA to replacedefective or deficient endogenous molecules, (c) angiogenic factorsincluding growth factors such as acidic and basic fibroblast growthfactors, vascular endothelial growth factor, epidermal growth factor,transforming growth factor α and β, platelet-derived endothelial growthfactor, platelet-derived growth factor, tumor necrosis factor α,hepatocyte growth factor and insulin-like growth factor, (d) cell cycleinhibitors including CD inhibitors, and (e) thymidine kinase (“TK”) andother agents useful for interfering with cell proliferation. Also ofinterest is DNA encoding for the family of bone morphogenic proteins(“BMP's”), including BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7(OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15,and BMP-16. Currently preferred BMP's are any of BMP-2, BMP-3, BMP-4,BMP-5, BMP-6 and BMP-7. These dimeric proteins can be provided ashomodimers, heterodimers, or combinations thereof, alone or togetherwith other molecules. Alternatively, or in addition, molecules capableof inducing an upstream or downstream effect of a BMP can be provided.Such molecules include any of the “hedgehog” proteins, or the DNA'sencoding them.

Vectors of interest for delivery of genetic therapeutic agents include(a) plasmids, (b) viral vectors such as adenovirus, adenoassociatedvirus and lentivirus, and (c) non-viral vectors such as lipids,liposomes and cationic lipids.

Cells include cells of human origin (autologous or allogeneic),including stem cells, or from an animal source (xenogeneic), which canbe genetically engineered if desired to deliver proteins of interest.

Among preferred therapeutic agents that may optionally be present in amedical device of the present invention include, but are not limited to,steroidal and non-steroidal anti-inflammatory agents (NSAIDs) andchemotherapeutic agents such asantineoplastic/antiproliferative/anti-mitotic agents, cytotoxic agents,cytostatic agents and cell proliferation affectors. Examples ofchemotherapeutic agents include cisplatin, methotrexate, doxorubicin,paclitaxel and docetaxel. Examples of steroidal anti-inflammatory agentsinclude dexamethasone, hydrocortisone and prednisone.

The therapeutic agent may be applied onto or into the device or anyportion thereof (the matrix polymer region or any optional barrierlayer, for example) by contacting the device or portion thereof with asolution or suspension of the therapeutic agent, for example byspraying, dipping, and so forth, followed by evaporating the solvent orcarrier liquid. The drug may also be incorporated during the processingand/or shaping of any of the matrix polymers and/or optional polymericbarrier layers used to form the medical device of the present inventionprovided that the drug is stable at the conditions (e.g., temperatureand pressure) required during such processing and/or shaping.

The amount of the therapeutic agent will be a therapeutically effectiveamount. As with the antimicrobial agent and microbial attachment/biofilmsynthesis inhibitor, the amount of any therapeutic agent present in amedical device will depend, inter alia, on the particular therapeuticagent, the length of time during which the medical device is intended toremain implanted, and the rate at which the therapeutic agent isreleased from the matrix polymer and/or barrier layer. The amount of thetherapeutic agent may be limited by the propensity of such agent tocause an undesirable localized or systemic toxic reaction and by theimpairment of mechanical properties necessary for proper functioning ofthe device.

The medical device of the present invention may comprise a multilayerstructure comprising from 2 to about 50 distinct layers, more preferablyfrom about 2 to about 20 layers formed by coextrusion as described morefully below. Preferred multilayer structures may have from about 2 toabout 7 distinct layers. Particularly preferred multilayer structureshave from about 3 to about 7 layers, with a 3 layer construction beingespecially preferred. As noted above, the medical device comprises oneor more matrix polymer regions. The medical device can also comprise oneor more barrier regions as well. Hence, in a multilayer construction,one or more of the distinct layers may be a barrier layer that leastpartially covers one or more matrix polymer layers. Thus, the medicaldevice of the present invention may comprise one or more layerscomprising one or more distinct matrix polymer layers and, if desired,one or more barrier layers.

Multilayer structures of the present invention need not comprise abarrier layer. For example, a medical device in accordance with thepresent invention may comprise a two-layer structure comprising a firstmatrix polymer layer containing the bioactive agents andradio-opacifying agent and a second layer on an external surface of thefirst matrix polymer layer wherein the second layer provides lubricity.Such a lubricious layer may be desirable, for example, to facilitateinsertion and implantation of the medical device.

It is understood that the medical device of the present invention is notlimited to a multiple layer structure and, indeed, a single layerstructure such as an annular tube comprising a matrix polymer, anantimicrobial agent, a microbial attachment/biofilm synthesis inhibitorand an optional radio-opacifying agent, is within the scope of thepresent invention.

Medical devices in accordance with the present invention having multiplelayer structures may provide certain advantages relative to single layerdevices, however. For example, a barrier layer can be provided tocontrol the rate of release of bioactive material or therapeutic agentfrom an adjacent layer, such a matrix polymer layer. The barrier layer,as described more fully below, may also be advantageous in substantiallyreducing the partitioning of a bioactive agent to the surface of amatrix polymer layer during processing. Multiple layers, such asdistinct matrix polymer layers, may also act as reservoirs for differentbioactive agents and/or combinations of a bioactive agent, aradio-opaque material and a therapeutic agent. Hence, the use ofmultiple layers may be advantageous in providing different releaseprofiles of different bioactive agents and/or therapeutic agents. Forexample, the release characteristics of a particular bioactive and/ortherapeutic agent may depend on its ability to diffuse from a particularmatrix polymer. Thus, different compositions of matrix polymer andbioactive and/or therapeutic agent may provide different releasecharacteristics therefrom. Some compositions may result in relativelyfast release while others may result in a relatively slower releaseprofile. By appropriate selection and arrangement of distinct layers ofmatrix polymer containing bioactive and/or therapeutic agents, therelease profile of the different bioactive and/or therapeutic agent fromthe device may be optimized for a particular application.

For example, in one embodiment of the present invention adapted toprovide controlled release of a bioactive and any optional therapeuticagents, there is provided a multilayer structure comprising a firstannular layer comprising a biocompatible matrix polymer, anantimicrobial agent, a microbial attachment/biofilm synthesis inhibitorand, optionally, a therapeutic agent. First and second barrier layers(also annular in shape) are disposed on the exterior and interiorsurfaces, respectively, of the first annular layer. The first and secondbarrier layers that enclose the first annular layer are typically lesspermeable than the biocompatible matrix polymer and, thereby, controlthe rate of diffusion of the bioactive and optional therapeutic agentsfrom the device to the external environment.

A simplified schematic representation of this embodiment of the presentinvention is depicted in FIG. 1. Implantable or insertable medicaldevice 100 in accordance with this embodiment of the present inventioncomprises an annular first matrix polymer region 101; an annular firstpolymeric barrier layer 111 at least partially covering an interiorsurface of first matrix polymer region 101 and, an annular secondpolymeric barrier layer 112 at least partially covering an exteriorsurface of first matrix polymer region 101. Annular first and secondpolymeric barrier layers 111 and 112, respectively, may have the same ora different composition.

The barrier layers preferably comprise polymeric materials. Any of thenon-biodegradable and biodegradable polymers described hereinabove inrelation to the matrix polymer may also form a barrier layer. Preferredbarrier layer polymers include, but are not limited to, ethyleniccopolymers such as ethylene vinyl acetate and copolymers of ethylenewith acrylic or methacrylic acid, elastomers including elastomericpolyurethanes and block and random copolymers thereof, metallocenecatalyzed polyethylene (mPE) and mPE copolymers, ionomers, silicones andmixtures thereof. Metallocene catalyzed polyethylenes and mPEcopolymers, such as copolymers of ethylene with octene, and ionomers andmay be particularly preferred polymeric barrier layer materials tocontrol partitioning of any bioactive agent such as salicylic acid orsodium salicylate to the surface of the matrix polymer during processingand to provide controlled release of active agents from the matrixpolymer.

A barrier layer and any contacting matrix polymer layer or region willpreferably comprise different polymeric materials. Different polymericmaterials will generally provide different rates of diffusion or releaseof bioactive agent. Thus, less permeable barrier layers may be providedto control the rate of release of a bioactive agent from a contactingmatrix polymer region which may be more permeable to diffusion of abioactive agent. For example, where an EVA copolymer having a vinylacetate content of from about 19% to about 28% is used as the matrixpolymer, an EVA copolymer having a lower vinyl acetate content of fromabout 3% to about 15% may be useful to form the contacting barrierlayer. Lower vinyl acetate content EVA copolymers are useful as barrierlayers because of their lower permeability, hence ability to releasebioactive agent more slowly than higher vinyl acetate contentcopolymers. The relative rigidity or stiffness of such lower vinylacetate content barrier layers may be offset somewhat by the use ofhigher vinyl acetate content matrix polymer layers or regions.

While two barrier layers are provided in medical device 100 depicted inFIG. 1, it is understood that a medical device of the present inventionmay comprise an annular matrix polymer region provided with no barrierlayer, or with a single barrier layer at least partially covering anexterior or interior surface of the annular matrix polymer region. It isalso understood that while annular matrix polymer regions and annularbarrier layers may be preferred in some embodiments of the presentinvention, neither any matrix polymer region nor any barrier layer needbe annular.

In the medical device depicted in FIG. 1, and the above-described andother modifications thereof in accordance with the present invention,the first matrix polymer region preferably comprises a biocompatiblematrix polymer as described herein, an antimicrobial agent, a microbialattachment biofilm synthesis inhibitor and, as optional components, oneor more of a radio-opacifying agent and a therapeutic agent.

Another embodiment of the present invention comprising a multi-layerstructure will now be described. In this embodiment, the device isdesigned to provide slower release of a bioactive and/or therapeuticagent from a first matrix polymer composition relative to release of abioactive and/or therapeutic agent from a second matrix polymercomposition. In this embodiment, there is provided an annular layer ofthe first matrix polymer composition between distinct annular layers ofthe second matrix polymer composition. In such a multilayerconfiguration, each surface of the second matrix polymer compositionthat would otherwise be exposed to the external environment is providedwith a barrier layer. Similarly, barrier layers are provided between theannular layer of the first matrix polymer composition and the annularlayers of the second matrix polymer composition. The resulting structurecomprises seven layers, three of which form distinct matrix polymerregions and four of which form barrier layers covering at least aportion of one or more surfaces of the matrix polymer regions. In thisconfiguration, the bioactive and/or therapeutic agent from the annularlayer comprising the first matrix polymer composition would have todiffuse through its own barrier layer, into and through an annular layercomprising the second matrix polymer composition and through anotherbarrier layer before reaching the external environment. This multi-layerconfiguration provides a slower release of bioactive and/or therapeuticagent from the annular layer of the first matrix polymer compositionrelative to the rate of release of bioactive and/or therapeutic agentfrom the annular layer of the second matrix polymer composition.

A simplified schematic representation of this embodiment of the presentinvention is depicted in FIG. 2. Implantable or insertable medicaldevice 200 in accordance with this embodiment of the present inventioncomprises annular first matrix polymer region 201; annular firstpolymeric barrier layer 211 at least partially covering an interiorsurface of first matrix polymer region 201; annular second polymericbarrier layer 212 at least partially covering an exterior surface offirst matrix polymer region 201; annular second matrix polymer region202 at least partially covering an exterior surface of annular secondpolymeric barrier layer 212; annular third polymeric barrier layer 213at least partially covering an exterior surface of annular second matrixpolymer region 202; annular third matrix polymer region 203 disposed onan interior surface of annular first polymeric barrier layer 211; andannular fourth polymer barrier layer 214 at least partially covering aninterior surface of annular third matrix polymer region 203.

Annular first, second, and third matrix polymer regions 201, 202 and203, respectively, may have the same or different compositions. In apreferred embodiment, annular second and third matrix polymer regions202 and 203, respectively, have the same composition which is differentfrom the composition of annular first matrix polymer region 201. In thispreferred embodiment, it is also preferred that annular first and secondpolymeric barrier layers 211 and 212, respectively, have the samecomposition and annular third and fourth polymer barrier layers 213 and214, respectively, have the same composition. In this embodiment, it isparticularly preferred that the annular first and second polymericbarrier layers 211 and 212, respectively, have a composition differentfrom that of the annular third and fourth polymeric barrier layers, 213and 214, respectively. However, more broadly, annular first, second,third and fourth polymeric barrier layers 211, 212, 213 and 214,respectively, may have the same or different compositions. Similarly,annular first, second and third matrix polymer regions 201, 202 and 203,respectively may have the same or different compositions.

Another embodiment of the present invention may also be described withreference to FIG. 2. In this embodiment, the medical device has twomatrix polymer regions and three polymeric barrier layers. Thisembodiment of the present invention may be envisioned by removing, fromthe medical device depicted in FIG. 2, annular third matrix polymerregion 203 and annular fourth polymer barrier layer 214, therebyresulting in a five layer structure comprising two distinct matrixpolymer regions (201, 202) and three polymeric barrier layers (211, 212,213) at least partially covering one or more surfaces of the distinctmatrix polymer regions.

It is understood that other configurations of barrier layers and matrixpolymer regions are within the scope of the present invention. Forexample, again with reference to FIG. 2, a five layer structure withinthe scope of the present invention may be envisioned by removing annularthird and fourth polymeric barrier layers, 213 and 214, respectively. Inthis embodiment, the resulting five layer structure will comprise threedistinct matrix polymer regions (201, 202, 203) separated from eachother by two barrier layers (211, 212) disposed on inner and outersurfaces of annular first matrix polymer region 201.

In the medical device depicted in FIG. 2, and the above-described andother modifications thereof in accordance with the present invention,any of the first, second and optional third matrix polymer regionspreferably comprises a biocompatible matrix polymer as described hereinand either or both of an antimicrobial agent and a microbial attachmentbiofilm synthesis inhibitor and, as optional components, one or more ofa radio-opacifying agent and a therapeutic agent.

The present invention is not to be construed as limited in any way bythe simplified schematic representations of the embodiments of thepresent invention as depicted in FIG. 1 or 2. Thus, a medical device inaccordance with the present invention can be a single layer ormultilayer construction; may have one or multiple matrix polymer regionsand may have none, one or multiple barrier layers. Moreover, neither anymatrix polymer region nor any barrier layer need be annular as depictedin the Figures. Further, where a barrier or other layer is provided inaddition to a matrix polymer layer, any of a bioactive agent, aradio-opacifying agent and a therapeutic agent may be provided in or onsuch barrier or other layer.

Further optimization of release profiles can be obtained by providing amultilayer structure having both biodegradable and substantiallynon-biodegradable layers. Matrix polymer layers having different ratesof biodegradation can, for example, provide different release profilesof bioactive and/or therapeutic agents. By appropriate selection andplacement of such biodegradable layers, release profiles can beoptimized based on the desired time-dependent requirements for releaseof such bioactive and/or therapeutic agents.

Multiple layers may also be provided to act as barrier layers toseparate, at least temporarily, otherwise incompatible polymers,bioactive agents, therapeutic agents and radio-opacifying agents. Forexample, such materials or agents may not be compatible with anothersuch material or agent under the processing conditions employed tomanufacture the medical device. As a specific example, an antimicrobialagent such as chlorhexidine may react with a microbialattachment/biofilm synthesis inhibitor such as salicylic acid when mixedwith an EVA copolymer under certain conditions in a twin screw extruder.The resultant chemical modification of the compounds may render themineffective for their intended purpose. As another example, aradio-opacifying agent such as bismuth subcarbonate may react with anantimicrobial agent such as salicylic acid under certain processingconditions necessary for a particular matrix polymer.

The use of a barrier layer is also advantageous in substantiallyreducing or preventing the preferential partitioning of a bioactiveagent to the surface of a medical device during or subsequent toprocessing. For example, a microbial attachment/biofilm synthesisinhibitor such as salicylic acid may preferentially partition to thesurface of a matrix polymer such as an EVA copolymer during orsubsequent to some of the processing steps involved in formation of themedical device. This preferential partitioning may be referred to as“blooming.” It is believed that blooming may result, at least in part,when the bioactive agent has limited solubility in the polymer,particularly as it is cooled after processing. Also, a bioactive agentthat has greater solubility in water than in a matrix polymer may bemore susceptible to blooming during processing of the matrix polymer andbioactive agent. It may, therefore, be desirable to control moisturecontent during processing of the bioactive agent and matrix polymer toprevent blooming of bioactive agent. In any event, blooming may resultin the appearance of crystals of the bioactive agent, such as salicylicacid, on the surface of the device within hours after processing.

In one embodiment of the present invention adapted to substantiallyreduce or prevent blooming, there is provided a multilayer structurecomprising a first annular layer comprising a biocompatible matrixpolymer, an antimicrobial agent, a microbial attachment/biofilmsynthesis inhibitor; and annular first and second barrier layers on theexterior and interior surfaces, respectively, of the first annular layer(as optional components, a radio-opacifying agent and/or a therapeuticagent may also be added to one or more of the layers). Blooming orpartitioning of a bioactive agent to a surface of the device can beeffectively controlled by providing the first and second annular barrierlayers in this embodiment. A medical device in accordance with thisembodiment comprising a three layer structure adapted to substantiallyreduce blooming may have a structure similar to that shown in FIG. 1,described hereinabove.

In another aspect, the present invention is directed to a method ofmanufacturing an implantable or insertable medical device comprising (a)providing one or more biocompatible matrix polymers, one or moreantimicrobial agents and one or more microbial attachment/biofilmsynthesis inhibitor and, optionally, one or more of a radio-opacifyingagent and/or a therapeutic agent; (b) processing the one or morebiocompatible matrix polymers and the bioactive agents, preferably underconditions that substantially prevent preferential partitioning of anyof the bioactive agents to a surface of any of the biocompatible matrixpolymers and that substantially prevent chemical modification of thebioactive agents.

Processing typically comprises mixing or compounding the matrix polymer,bioactive agents and optional radio-opacifying and/or therapeutic agentsto form a homogeneous mixture thereof and shaping the homogenous mixtureinto a matrix polymer region of an implantable or insertable medicaldevice. The mixing and shaping operations, as described more fullybelow, may be performed using any of the conventional devices known inthe art for such purposes. In the following description, the one or morebioactive agents and optional radio-opacifying and/or therapeutic agentswill, at times, be collectively referred to as “additives” or “agents.”

During processing, there exists the potential for one of more of thepolymer matrix material, bioactive agents and optional radio-opacifyingand/or therapeutic agents to become chemically modified bycross-reacting with one another. These undesirable cross-reactions mayresult from the incompatibility or instability of these agents at theelevated temperatures typically involved during the processing. It isalso believed that excessive moisture content during processing mayfacilitate chemical modification of the agents.

Excessive moisture content can also facilitate blooming of a bioactiveagent to a surface of a matrix polymer. Other processing conditions canalso result, as discussed hereinabove, in blooming of one or more of thebioactive agents to the surface of a matrix polymer during and/orsubsequent to processing.

Hence, processing is preferably performed under conditions thatsubstantially prevent preferential partitioning of any of the agents andsubstantially prevent chemical modification of the agents. It isunderstood that some partitioning and chemical modification may beunavoidable during processing. Therefore, by “substantially prevent” ismeant that no more than about 25% by weight, preferably less than about10% by weight (based on the weight of the matrix polymer composition),of any bioactive agent is preferentially partitioned to a surface of amatrix polymer and/or chemically modified during processing.

Among the processing conditions that may be controlled during processingto substantially reduce the risk of partitioning and/or chemicalmodification are the temperature, moisture content, applied shear rateand residence time of the mixture of matrix polymer, bioactive agents,and optional radio-opacifying and/or therapeutic agents in a processingdevice.

Mixing or compounding a matrix polymer with one or more of the bioactiveagents and optional radio-opacifying and/or therapeutic agents to form ahomogeneous mixture thereof may be performed with any device known inthe art and conventionally used for mixing polymeric materials withadditives. Where thermoplastic materials are employed, a polymer melt isformed by heating the various agents, which can then be mixed to form ahomogenous mixture. A common way of doing so is to apply mechanicalshear to a mixture of the matrix polymer and additives. Devices in whichthe matrix polymer and additives may be mixed in this fashion include,but are not limited to, devices such as a single screw extruder, a twinscrew extruder, a banbury mixer, a high-speed mixer, and a ross kettle.

Mixing may also be achieved by dissolving the matrix polymer with one ormore of the bioactive agents and optional radio-opacifying and/ortherapeutic agents in a solvent system or forming a liquid dispersion ofthe same.

Any of the matrix polymer and/or additives may be precompounded orindividually premixed to facilitate subsequent processing. For example,a radio-opacifying agent may be precompounded with a matrix polymer andthen mixed with any bioactive agent. Alternatively, the radio-opacifyingagent such as bismuth subcarbonate may be preblended with any bioactiveagent in a device such as a v-mixer with an intensifier bar before beingmixed with the matrix polymer.

In some preferred embodiments, a homogenous mixture of the matrixpolymer and additives is produced using a twin screw extruder, such as atwin screw extruder with a low-shear profile design. Barrel temperature,screw speed and throughput are typically controlled to preventpartitioning and chemical modification as discussed hereinabove.

The conditions necessary to achieve a homogenous mixture of the matrixpolymer and additives during compounding will depend, to some extent, onthe specific matrix polymer as well as the type of mixing device used.For example, different matrix polymers will typically soften into a meltto facilitate mixing at different temperatures. It is generallypreferred to mix the matrix polymer and additives at a temperature fromabout 60° C. to about 140° C., more preferably from about 70° C. toabout 100° C., most preferably from about 80° C. to about 90° C. Thesetemperature ranges have been found to result in formation of ahomogenous mixture of the matrix polymer and additives, whilesubstantially preventing partitioning and chemical modification. Somecombinations of matrix polymer and additive can be processed at a lowertemperature than might otherwise be expected to result in homogeneousmixing. For example, while

70° C. may be a relatively low temperature for processing an EVAcopolymer and an additive, an antimicrobial agent such as triclosan,which melts at a temperature of around 50° C., may act as a plasticizerfor the EVA, facilitating use of a lower temperature of about 70° C. Theability to process the EVA at a lower temperature by virtue of anadditive acting as a plasticizer advantageously reduces the risk ofchemical modification of the additives if a higher temperature wereotherwise required. Higher temperatures may be employed, however, duringsubsequent shaping of the homogenous mixture into a portion of a medicaldevice as described herein. For example, higher temperatures may benecessary in localized portions of a coextrusion device used to apply abarrier layer onto one or more surfaces of the matrix polymer. However,the time at which the higher temperatures are encountered by the mixtureare generally kept to a minimum.

The mixture of matrix polymer and additives can be shaped into at leasta portion of a medical device in accordance with the present inventionby means of any process conventionally used to shape polymeric materialssuch as thermoplastic and elastomeric materials. Among such shapingprocesses are included, but not limited to, extrusion includingcoextrusion, molding, calendaring, casting and solvent coating. Amongpreferred shaping processes are extrusion and coextrusion processes.

Coextrusion is a particularly preferred shaping process wherein at leasta portion of a medical device in accordance with the present inventionis a multilayer structure, for example, comprising one or more distinctmatrix polymer regions and one or more barrier layers at least partiallycovering a surface of a matrix polymer region. Among preferredcoextruded multilayer structures are those having 3 to 7 distinct layersas described hereinabove. Especially preferred coextruded structures arethose in which each of the matrix polymer regions and contactingbarriers layers have annular shapes. For example, a three layerstructure may be formed by coextruding annular polymeric barrier layerswith an annular matrix polymer region such that the polymeric barrierlayers at least partially cover interior and exterior surfaces of thematrix polymer region. Two, five, and seven layer constructions asdescribed herein may be similarly formed by coextrusion, as can anymultilayer construction having from 2 to about 50 layers. It is alsounderstood that a medical device of the present invention may be formedby extruding a single annular matrix polymer containing bioactiveagents, an optional radio-opacifying agent and an optional therapeuticagent. Multi-layer structures can also be formed by other processing andshaping techniques such as laminar injection molding (LIM) technology.

The temperatures used for shaping the matrix polymer and any barrierlayers will, of course, depend on the particular materials used and theshaping device employed. Shaping process conditions, as with the mixingor compounding process conditions, may also result in undesirablepartitioning and/or cross-reactions. Therefore, control of any shapingprocess condition such as temperature, moisture content, shear rate andresidence time may be desirable to avoid partitioning and/orcross-reactions.

For example, a three layer structure comprising an annular matrixpolymer region and two barrier layers covering an interior and exteriorsurface, respectively, of the matrix polymer region may be formed bycoextruding the matrix polymer containing the bioactive agents andoptional radio-opacifying agent and/or therapeutic agent. In such acoextrusion process, the barrel and shaping die temperatures, screwspeed and compression ratio, may be controlled to prevent undesirablepartitioning and chemical modification of the bioactive agents. Forexample, coextrusion of a 19% vinyl acetate EVA copolymer as a matrixpolymer, compounded with 10% by weight triclosan, 10% by weightsalicylic acid and 30% by weight bismuth subcarbonate may be coextrudedwith two layers of a metallocene catalyzed polyethylene (“mPE”)copolymer such as an ethylene-octene copolymer (24% octene co-monomer)serving as barrier layers. In such a coextrusion process, a screw speedof 35 rpm on a 3:1 compression ratio, using a 1″ screw diameter with nomixing section and a barrel temperature of about 110° C. was found to besufficient to substantially prevent cross-reactions and bioactive agentpartitioning. As alluded to above, barrier layer materials may requirehigher processing temperatures during shaping than temperatures employedduring compounding of the matrix polymer and additives. Consequently, itmay be necessary to maintain portions of the extrusion apparatus athigher temperatures than employed during compounding. In thisembodiment, a barrel temperature of about 110° C. and a shaping headtemperature of about 150° C. are employed to facilitate formation of themPE copolymer barrier layers. While these temperatures are higher thanthe temperature (about 70° C.) used to compound the EVA matrix polymerand additives, substantial partitioning and chemical modification of thebioactive agents may, nonetheless, be avoided, due in part to the shortresidence time at these temperatures.

Other shaping processes, as mentioned above, include extrusion coatingand solvent coating. For example, a barrier layer polymer could beextruded onto a preformed matrix polymer region. This process isdistinguished from a coextrusion process in which the matrix polymer andbarrier layers are shaped substantially simultaneously. Alternatively, abarrier layer could be applied to a surface of a matrix polymer byapplying a solvent solution or liquid dispersion of a barrier polymeronto a surface of the matrix polymer followed by removing the solvent orliquid dispersing agent, e.g., by evaporation. Such a solution ordispersion of the barrier polymer may be applied by contacting a surfaceof the matrix polymer with the solution or dispersion by, for example,dipping or spraying. The use of these other shaping processes are notlimited to the application of a barrier layer to a matrix polymerregion. Therefore, a matrix polymer region may also be formed onto apreformed substrate by similar methods.

The medical device of the present invention may be any implantable orinsertable medical device, particularly one that may be susceptible tomicrobial growth on and around the surfaces of the device, includingattachment of microbes onto and the synthesis by attached microbes ofbiofilm on the surface of the medical device. Preferred implantablemedical devices include those adapted to remain implanted for arelatively long-term, i.e., for period of from about 30 days to about 12months or greater. However, devices intended to remain implanted forabout 30 days or less are also included within the scope of the presentinvention.

Examples of implantable medical devices include, but are not limited to,stents, stent grafts, stent covers, catheters, artificial heart valvesand heart valve scaffolds, venous access devices, vena cava filters,peritoneal access devices, and enteral feeding devices used inpercutaneous endoscopic gastronomy, prosthetic joints and artificialligaments and tendons. Preferred medical devices include those adaptedto bridge or provide drainage between two sterile areas of the body orbetween a sterile and non-sterile area of the body. Devices adapted tobridge or provide drainage between a sterile and a non-sterile area ofthe body are particularly susceptible to microbial growth, attachmentand biofilm formation due to contamination of the sterile area frommicrobes normally present in the non-sterile area. Medical devicesintended to be implanted in or bridge sterile body environments may besusceptible to microbial growth, attachment and biofilm formation, forexample, from microbial organisms that are ordinarily present in thenon-sterile area (i.e., non-pathogenic organisms), from those that arepresent due to disease, (i.e., pathogenic organisms) and from thoseintroduced during the insertion or implantation of the medical device.

Stents include biliary, urethral, ureteral, tracheal, coronary,gastrointestinal and esophageal stents. Preferred stents include biliarystents, ureteral stents and pancreatic stents. The stents may be of anyshape or configuration. The stents may comprise a hollow tubularstructure which is particularly useful in providing flow or drainagethrough biliary and ureteral lumens. Stents may also be coiled orpatterned as a braided or woven open network of fibers or filaments or,for example, as an interconnecting open network of articulable segments.Such stent designs may be more particularly suitable for maintaining thepatency of a body lumen such as a coronary artery. Thus, stents adaptedprimarily to provide drainage, in contrast to stents adapted primarilyto support a body lumen, will preferably have a continuous wallstructure in contrast to an open network wall structure.

Stent covers are also a preferred medical device of the presentinvention. For example, a stent cover may comprise a thin wall tubularor sheath-like structure adapted to be placed over a stent comprising anopen mesh stent of knitted, woven or braided design. A preferred stentcover is adapted to be placed over a biliary stent. The biliary stentcan be made of any material useful for such purpose including metallicand non-metallic materials as well as shape memory materials. Amonguseful metallic materials include, but are not limited to, shape memoryalloys such as Nitinol®, and other metallic materials including, but notlimited to, stainless steel, tantalum, nickel-chrome, orcobalt-chromium, i.e., Elgiloy®. The biliary stent can be made from asingle strand or multiple strands of any such material and may beself-expanding. The stent cover may comprise a matrix polymer asdescribed herein which comprises an antimicrobial agent such astriclosan, a microbial attachment/biofilm synthesis inhibitor such assalicylic acid and a radio-opacifying agent such as bismuthsubcarbonate. A particularly preferred stent cover comprises anelastomeric polyurethane or polyurethane copolymer as described above.The stent cover is particularly advantageous in reducing tissue growththrough an open mesh stent while at the same time reducing microbialgrowth on and around the surface of the stent, reducing attachment ofmicrobes onto the stent, and reducing the synthesis of biofilm on thesurface of the stent.

Another preferred medical device of the present invention is apancreatic stent that provides drainage from the pancreas to theduodenom. Normally, the pancreas drains into the duodenum by thepancreatic duct. Implantable pancreatic drainage devices are sometimesdesired to alleviate problems such as strictures, sphincter stenoses,obstructing stones or to seal duct disruptions. However, when thepancreatic duct is opened, or an implantable medical device is placed inthe pancreas, morphological changes may occur that may lead topancreatitis.

It is believed that morphological changes in the pancreas upon insertionof an implantable medical device may be related to the pH differencebetween a normal pancreas and the duodenum into which the pancreasdrains. The pancreas has a higher pH than the duodenum and excretesaqueous bicarbonate to buffer the duodenum. The implantation of amedical device into the pancreas may substantially reduce the ability oreffectiveness of the pancreas to provide this buffering action,potentially leading to undesirable morphological changes in thepancreas.

It is believed that by providing a pancreatic stent that releases abuffering agent so as to create a pancreatic pH level in the environmentof the implanted medical device, undesirable morphological changes inthe pancreas may be substantially reduced or even prevented. This may beaccomplished by providing an agent in or on the surfaces of a pancreaticstent such that when the pancreatic stent is exposed to physiologicalfluids, the buffering agent is released from the stent creating alocally higher pH environment around the device. Among buffering agentsare included, but not limited to, bicarbonate salts such as sodium orpotassium bicarbonate. Such buffering agents may be incorporated, forexample, in a matrix polymer in a manner described hereinabove withrespect to bioactive agents, or they may be applied as a coating on asurface of a matrix polymer, or they may be applied in or as a coatingon any optional barrier layer by any of the methods described above.

The invention will be further described with reference to the followingnon-limiting Examples. It will be apparent to those skilled in the artthat many changes can be made in the embodiments described in suchExamples, consistent with the foregoing description, without departingfrom the scope of the present invention.

Example 1

A single-layer matrix polymer structure is formed from a mixturecontaining an ethylene vinyl acetate (EVA) copolymer having a 19% vinylacetate content, 10% triclosan by weight of the mixture as anantimicrobial agent, 10% salicylic acid by weight of the mixture as amicrobial attachment/biofilm synthesis inhibitor, and 30% bismuthsubcarbonate by weight of the mixture as a radio-opacifying agent. Thebismuth subcarbonate is precompounded with the EVA copolymer (62.5%EVA/37.5% bismuth subcarbonate) and added to the triclosan and salicylicacid bioactive agents. Alternatively, the bismuth subcarbonate ispreblended with the triclosan and salicylic acid in a v-mixer withintensifier bar before adding to the polymer. A v-blender with anapproximately 13 rpm shell speed and a pin-type intensifier bar at about120 rpm for about 15 minutes produces a consistent, homogenous powderblend. The triclosan, salicylic acid and bismuth subcarbonate arecompounded with the EVA copolymer in an 18 mm screw diameter twin screwextruder with a low-shear profile screw design. The barrel temperaturein the screw is about 70° C. with a screw speed of about 200 rpm and athroughput of about 3.5 kg/hr. Since 70° C. is a relatively lowprocessing temperature for EVA, the triclosan acts as a plasticizer tofacilitate compounding and subsequent extrusion. After compounding, themixture is extruded into tubes in a standard 1″ screw diameter extruderwith a 24:1 L/D, 3:1 compression ratio, low shear screw. Maximum barreltemperature is about 100° C. to prevent reaction between the bismuthsubcarbonate and the salicylic acid. The screw speed is kept relativelylow, around 20 rpm, to keep the shear rate low and prevent excessviscous heat dissipation.

Example 2

A three-layer structure is formed having a matrix polymer region withthe same composition and compounding as described in Example 1, andcoextruded with barrier layers covering the inner and outer surfaces ofthe matrix polymer region. The barrier layers are formed of anethylene-octene copolymer in which the octane co-monomer content isabout 24%. Each of the barrier layers forms about 5% of the total wallthickness of the three-layer structure. Thicker or thinner barrierlayers may be provided to retard or increase the release rate of thebioactive agents from the matrix polymer. The compounded matrix polymerand barrier layers are coextruded while controlling the screw speed andtemperature to avoid overheating and undesirable cross-reactions and theconsequent chemical modification of the bioactive agents and/orradio-opacifying agent. The coextrusion is performed using a screw speedof about 35 rpm on a 3:1 compression ratio, a 1″ diameter screw with nomixing section. A barrel temperature of about 110° C. was found tosubstantially prevent cross-reactions. The copolymer barrier layersrequire higher processing temperatures at the shaping die at the head ofthe extruder. A shaping die temperature of about 150° C. was found toprovide adequate head pressure, layer quality and cross-reaction at theshaping die.

Example 3

Approximately 2 cm lengths of extruded 19% vinyl acetate EVA copolymertubing containing varying amounts of triclosan (TCN), salicylic acid(SA) and bismuth subcarbonate (BsC) are incubated in phosphate bufferedsaline (PBS) at 37° C. for 0 (“no treatment”), 3, 8 and 28 days. Thepurpose of incubation in PBS is to show longevity of SA inhibition onbacterial attachment after exposure, and release of SA from the extrudedtube. After incubation in PBS, the tubes are exposed a solutioncontaining approximately 10⁻⁴ to 10⁻⁵ cfu/ml E. coli for about 4 hr at37° C. with rotation at about 100 rpm. Subsequent to this exposure, thesamples are rinsed in saline and “rolled” following an establishedpattern onto a standard Mueller-Hinton agar plate. The plates areincubated for about 18 to 24 hr to allow colonies to form. The coloniesare counted and expressed as cfu per inch of tube.

FIG. 3 shows the normalized inhibitory response of the tubes. Theamounts of TCN, SA and BsC in the tubes are represented as % TCN/% SA/%BsC (wt % based on weight of vinyl acetate EVA copolymer). Therefore, atube having 10% TCN, 0% SA and 30% BsC is designated in FIG. 3 as“10/0/30”. FIG. 3 shows the inhibitory response of five tubes havingvarying weight percentages of TCN and SA and 30% BsC, normalized to a10/0/30 tube, given an inhibitory response value of 1. FIG. 3 shows thattubes containing 10% TCN and varying amounts (1%, 3% and 10% SA)inhibited bacterial attachment more effectively than tubes containingonly TCN (“10/0/30”) and inhibited bacterial attachment more effectivelythan tubes containing neither TCN nor SA (“0/0/30”). FIG. 3 also showsthat, as the amount of SA increased from 0% to 10%, with TCN constant at10%, the tubes were generally more effective at inhibiting bacterialattachment, suggesting that SA provides a synergistic effect. FIG. 3further shows that incubation of the tubes in PBS prior to exposure toE. coli did not significantly affect bacterial inhibition, suggestingthat effective amounts of TCN and SA remained in the extruded tubesafter extended incubation in PBS, i.e., that the bioactive agents werenot excessively or prematurely leached out of the extruded tubes. FIG. 4shows results (not normalized) for similar tubes incubated for 3 and 8days in PBS prior to exposure to E. coli.

Example 4

Approximately 2 cm lengths of extruded 19% vinyl acetate EVA copolymertubing containing varying amounts of triclosan (TCN), salicylic acid(SA) and bismuth subcarbonate (BsC) are inserted into an agar lawn ofeither E. coli (FIG. 5) or staph (FIG. 6). The tubes are positioned soas to extend vertically upwardly from the surface of the agar lawn(similar to birthday candles). After 24 hours in the agar lawn, the zone(diameter) of bacterial growth inhibition around the tubes is measured.The tubes are repositioned in fresh agar plates every 24 hours, and thezone of bacterial growth inhibition is again measured. FIG. 5 shows themeasurement results for the tubes positioned in the agar lawn of E. coliand FIG. 6 shows the results for the tubes positioned in the agar lawnof staph. FIGS. 5 and 6 show that the zone of bacterial growthinhibition was larger as the percentage of TCN increased from 0% to amaximum of 10%. A tube containing no TCN, but varying amounts of SA didnot effectively inhibit bacterial growth, suggesting that bacterialgrowth inhibition (as opposed to inhibition of bacterial attachment) ispredominantly provided by TCN. FIGS. 5 and 6 also show that, for a givenpercentage of TCN, the measured zone of bacterial growth inhibition issimilar over a period extending to about 40 days or longer, suggestingthat the TCN component in the extruded tubes effectively maintains itsactivity for extended periods of time.

The invention may be embodied in other specific forms without departingfrom its proper scope. The described embodiments and Examples are to beconsidered in all respects only as illustrative and not restrictive. Thescope of the invention is, therefore, indicated by the appended claimsrather than by the foregoing description. All changes that come withinthe meaning and range of equivalency of the claims are to be embracedwithin their scope.

1. An implantable medical device comprising (a) at least onebiocompatible matrix polymer region and (b) bioactive agents comprisingan antimicrobial agent and a microbial attachment/biofilm synthesisinhibitor.
 2. The medical device of claim 1, wherein said antimicrobialagent is present in an amount effective to inhibit the growth ofmicrobes on and around the device and the microbial attachment/biofilmsynthesis inhibitor is present in an amount effective to inhibit theattachment of microbes onto and the synthesis and accumulation ofbiofilm from attached microbes on the surface of the device.
 3. Themedical device of claim 1, wherein said device is adapted to remainimplanted for a period of greater than about 30 days.
 4. The medicaldevice of claim 1, wherein said matrix polymer comprises a biocompatiblenon-biodegradable polymer.
 5. The medical device of claim 4, whereinsaid non-biodegradable polymer is an ethylene vinyl acetate copolymer.6. The medical device of claim 1, wherein said antimicrobial agent isselected from the group consisting of triclosan and chlorhexidine andmixtures thereof.
 7. The medical device of claim 6, wherein saidantimicrobial agent is triclosan.
 8. The medical device of claim 7,wherein said microbial attachment/biofilm synthesis inhibitor isselected from the group consisting of NSAIDs, EDTA and EGTA.
 9. Themedical device of claim 8, wherein said microbial attachment/biofilmsynthesis inhibitor is salicylic acid or a salt or derivative thereof.10. The medical device of claim 9, wherein said microbialattachment/biofilm synthesis inhibitor is salicylic acid.
 11. Themedical device of claim 1, wherein said matrix polymer further comprisesa radio-opacifying agent.
 12. The medical device of claim 11, whereinsaid radio-opacifying agent comprises bismuth subcarbonate.
 13. Themedical device of claim 1, wherein the matrix polymer further comprisesat least one therapeutic agent.
 14. The medical device of claim 13,wherein the therapeutic agent is selected from the group consisting ofchemotherapeutic agents, NSAIDs, steroidal anti-inflammatory agents, andmixtures thereof.
 15. The medical device of claim 13, wherein thetherapeutic agent is selected from the group consisting of cisplatin,methotrexate, doxorubicin, paclitaxel, docetaxel, dexamethasone,hydrocortisone and prednisone.
 16. The medical device of claim 1,further comprising one or more barrier layers at least partiallycovering said at least one matrix polymer region.
 17. The medical deviceof claim 1, wherein the medical device is selected from the groupconsisting of a stent cover, a biliary stent, a ureteral stent, apancreatic stent, a urinary catheter, a venous access device, aperitoneal access device, a device connecting or providing drainagebetween two sterile body environments, and a device connecting orproviding drainage between a non-sterile and a sterile body environment.18. The medical device of claim 17, wherein the device comprises adevice connecting or providing drainage between a non-sterile and asterile body environment.
 19. The medical device of claim 18, whereinthe device comprises a hollow tubular structure.
 20. The medical deviceof claim 17, wherein the device comprises a stent cover.
 21. Animplantable or insertable medical device comprising at least onebiocompatible matrix polymer region comprising a material selected fromthe group consisting of ethylene vinyl acetate copolymers, copolymers ofethylene with acrylic acid or methacrylic acid, metallocene catalyzedpolyethylenes and polyethylene copolymers, ionomers, vinyl aromaticcopolymers, elastomeric polyurethanes and polyurethane copolymers,silicones and mixtures thereof bioactive agents comprising anantimicrobial agent selected from the group consisting of triclosan,chlorhexidine and mixtures thereof a microbial attachment/biofilmsynthesis inhibitor selected from the group consisting of salicylic acidand salts and derivatives thereof and, a radio-opacifying agent selectedfrom the group consisting of bismuth subcarbonate, bismuth oxychloride,bismuth trioxide, barium sulfate, tungsten and mixtures thereof.